Skip Navigation LinksHome > September 2000 - Volume 93 - Issue 3 > Physostigmine Reverses Propofol-induced Unconsciousness and...
Anesthesiology:
Clinical Investigations

Physostigmine Reverses Propofol-induced Unconsciousness and Attenuation of the Auditory Steady State Response and Bispectral Index in Human Volunteers

Meuret, Pascal M.D.*; Backman, Steven B. M.D.C.M., Ph.D., F.R.C.P.C.†; Bonhomme, Vincent M.D.*; Plourde, Gilles M.D., M.Sc.†; Fiset, Pierre M.D., F.R.C.P.C.†

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: It is postulated that alteration of central cholinergic transmission plays an important role in the mechanism by which anesthetics produce unconsciousness. The authors investigated the effect of altering central cholinergic transmission, by physostigmine and scopolamine, on unconsciousness produced by propofol.
Methods: Propofol was administered to American Society of Anesthesiologists physical status 1 (n = 17) volunteers with use of a computer-controlled infusion pump at increasing concentrations until unconsciousness resulted (inability to respond to verbal commands, abolition of spontaneous movement). Central nervous system function was assessed by use of the Auditory Steady State Response (ASSR) and Bispectral Index (BIS) analysis of electrooculogram. During continuous administration of propofol, reversal of unconsciousness produced by physostigmine (28 μg/kg) and block of this reversal by scopolamine (8.6 μg/kg) were evaluated.
Results: Propofol produced unconsciousness at a plasma concentration of 3.2 ± 0.8 (± SD) μg/ml (n = 17). Unconsciousness was associated with reductions in ASSR (0.10 ± 0.08 μV [awake baseline 0.32 ± 0.18 μV], P < 0.001) and BIS (55.7 ± 8.8 [awake baseline 92.4 ± 3.9], P < 0.001). Physostigmine restored consciousness in 9 of 11 subjects, with concomitant increases in ASSR (0.38 ± 0.17 μV, P < 0.01) and BIS (75.3 ± 8.3, P < 0.001). In all subjects (n = 6) scopolamine blocked the physostigmine-induced reversal of unconsciousness and the increase of the ASSR and BIS (ASSR and BIS during propofol-induced unconsciousness: 0.09 ± 0.09 μV and 58.2 ± 7.5, respectively; ASSR and BIS after physostigmine administration: 0.08 ± 0.06 μV and 56.8 ± 6.7, respectively, NS).
Conclusions: These findings suggest that the unconsciousness produced by propofol is mediated at least in part via interruption of central cholinergic muscarinic transmission.
IT is postulated that alteration of central cholinergic transmission may play an important role in the mechanism by which general anesthetic drugs produce unconsciousness. 1,2 Data from sleep–wake studies in humans 3,4 and animals 5,6 strongly implicate altered central cholinergic transmission in mediating changes in the level of consciousness associated with the sleep–wake cycle. By analogy, it is argued that altered central cholinergic transmission also mediates the loss of consciousness induced by anesthetic drugs. 2 This argument is supported by results from animal studies, which show that anesthetic agents reduce acetylcholine turnover and release 7–10 and inhibit cholinergic nicotinic and muscarinic transmission. 11–17
Drugs specifically affecting central cholinergic transmission are exploited clinically to alter the level of consciousness of patients. For example, scopolamine, a competitive nonselective muscarinic antagonist that crosses the blood–brain barrier, is administered preoperatively to induce sedation, and high doses can produce unconsciousness as part of the central anticholinergic syndrome. 18 Physostigmine, an anticholinesterase inhibiting drug that crosses the blood–brain barrier, has been used to reverse the central anticholinergic syndrome 19 and the central nervous system (CNS) depressant effects of a variety of anesthetic drugs. For example, physostigmine decreases the time necessary for return to consciousness after anesthesia with use of halothane 20 and ketamine, 21 and reverses prolonged postoperative somnolence after induction of anesthesia with use of midazolam. 22 A case report describes a patient who showed delayed arousal after administration of halothane and in whom physostigmine produced abrupt awakening after 2 min. 23 Physostigmine also diminishes the time to recover cognitive function after sedation induced by meperidine, propiomazine, and scopolamine administered to parturients. 24 Physostigmine has recently been shown to increase the dose of propofol necessary to induce loss of consciousness. 25
These clinical observations are difficult to interpret because of multiple confounding variables, including administration of more than one drug, different end points used to assess the level of consciousness, and an unknown, inconsistent and varying level of anesthetic drug at CNS target sites. In the current study, we investigated the effect of altering central cholinergic transmission on unconsciousness produced by propofol in healthy human volunteers.
Back to Top | Article Outline

Methods

Subjects
After approval by the Royal Victoria Hospital Ethics Board, 17 American Society of Anesthesiologists physical status I paid volunteers (18–35 yr [24.9 ± 4.6 yr]; 7 men and 10 women) were recruited. Causes for exclusion, in otherwise healthy volunteers, included anticipated difficulty with tracheal intubation or mask ventilation, obesity, history of gastroesophageal reflux, and drug or alcohol abuse. Subjects gave written consent and underwent a complete medical evaluation (history, physical examination, and blood tests including complete blood count, biochemistry and β-human chorionic gonadotropin (βHCG) level [women]) before participation. Subjects had no history of neurologic or hearing disorders. Otoscopy and pure tone audiometry results were normal (MA40; Maico Hearing Instruments, Minneapolis, MN). Participants were required to fast for a minimum of 8 h before testing, which always occurred in the morning.
Back to Top | Article Outline
Anesthesia Monitoring
An 18G Jelco catheter (Ethicon Inc., Arlington, TX) was inserted into a large vein in the right forearm for drug administration, and a 20-gauge catheter was inserted into the right radial artery for blood sampling and monitoring of systemic arterial pressure. Additional monitoring included electrocardiography (3-lead), pulse oximetry, and concentration of expired carbon dioxide sampled through use of nasal prongs.
Back to Top | Article Outline
Design
Initial baseline (awake) auditory steady state response (ASSR), Bispectral Index (BIS), and behavioral and electroocculogram (EOG) responses to verbal command were determined and a blood sample was obtained for plasma propofol concentration analysis, as a control check for zero-concentration. Plasma propofol level was determined using high-performance liquid chromatography 26 (HPLC; duplicate assay for each determination). Propofol was administered with a computer-controlled Harvard 22 syringe pump (Harvard Apparatus, Inc., South Natick, MA) with use of the infusion program STANPUMP (Dr. S. Shafer, Stanford University, Palo Alto, CA) and pharmacokinetic data of Tackley et al.27 The STANPUMP program incorporates 28 an effect-site equilibration constant (keo) of 0.25 min−1 (t1/2 keo = 2.8 min). 29 Published t1/2 keo values for propofol range 28 from 1.5 to 3.3 min. An initial plasma concentration of 1.0 μg/ml was targeted, followed by a 10-min period for blood–brain equilibration. If subjects were still awake, or if they displayed spontaneous movement, the infusion rate was increased to achieve increases in plasma concentration of 1.0-μg/ml increments (each followed by a 10-min equilibration period) until loss of consciousness was produced and subjects were motionless. The requirement that subjects remain motionless during the study helped to reduce the likelihood of difficulty in evaluating responsiveness to verbal command and to eliminate movement artifact, which could contaminate ASSR, EOG, and BIS recordings. Assessment of responsiveness to verbal commands, electrophysiolgic recordings, and blood samples for propofol assay were obtained after loss of consciousness.
With loss of consciousness maintained by the continuous administration of propofol at a rate producing a stable target plasma concentration, subjects received an injection of saline (control) or physostigmine (28 μg/kg) + glycopyrrolate (4.2 μg/kg) in a random, double-blind order (n = 11). The dose of physostigmine was that which has been used clinically to reverse the sedative effects of anesthesia and the central anticholinergic syndrome. 18,20–25 Glycopyrrolate was administered with physostigmine to block the peripheral muscarinic side effects of the anticholinesterase. After injection of saline or physostigmine–glycopyrrolate, ASSR and BIS were measured and the level of consciousness assessed by the behavioral and EOG responses to verbal commands. Subsequently, the propofol infusion was discontinued, and ASSR and BIS values were determined after return to consciousness.
In six additional subjects, the effect of scopolamine pretreatment on the physostigmine-induced return to consciousness was assessed. The experimental protocol was similar to that described previously herein, except that after loss of consciousness was produced, scopolamine (8.6 μg/kg) was administered, followed by a 1-h delay before the administration of physostigmine and glycopyrrolate (28 μg/kg and 4.2 μg/kg, respectively). The dose of scopolamine (8.6 μg/kg) is in the range of that used clinically to produce sedation and has been shown to depress cognitive function in humans. 30–32 The administration of scopolamine 1 h before physostigmine is based on the latency to its peak amnesic effect 30 and on our unpublished observation that scopolamine reduces the amplitude of the ASSR and BIS maximally at 60–70 min.
Back to Top | Article Outline
Assessment of Level of Consciousness
Consciousness was assessed by the responsiveness to the spoken verbal commands “open your eyes” and “squeeze my fingers.” The commands were spoken in a loud voice and repeated up to 3 times if the subject did not respond. To objectively evaluate responsiveness, the electroocculogram produced in response to prerecorded, digitized (digitizing frequency: 16 kHz, 16-bit resolution) commands “open your eyes” and “close your eyes” was measured. The commands were presented to the right ear via an inserted earphone at an intensity of 70 dB (SPL; Bruel-Kjaer sonometer, model 2203; Bruel-Kjaer, Naerum, Denmark, and Norcross, GA) 5 times at 6-s intervals. The signal recorded from gold-cup electrodes placed above and below the right orbit (impedance < 3 kΩ) was amplified (model 12A5; Grass Instruments, Inc., Quincy, MA; bandpass, 0.1–30 Hz), digitized (90 Hz for 5,277 ms) and stored on disk for off-line analysis. Only the response to the “open your eyes” command was measured. The “close your eyes” command was used to ensure that the subject closed the eyes before the “open your eyes” command. The five tracings from each assessment were evaluated individually and averaged. The onset latency was measured from the average tracing at the start of the deflection indicating eye opening.
Back to Top | Article Outline
Auditory Steady State Response and Bispectral Index
Gold-cup electrodes filled with conductive gel were affixed to the scalp with use of collodion-impregnated gauze for recording the ASSR and BIS (impedance < 3 kΩ). An insert earphone (“E-A-R TONE” 3A; Cabot Corp., Indianapolis, IN) was placed in the right ear for delivery of tone bursts or verbal commands. A nonactive earphone was placed in the left ear to attenuate ambient sound. A computer (Intel Pentium microprocessor; Intel, Santa Clara, CA) equipped with two analog-to-digital–digital-to-analog cards (DT2821 series; Transduction, Mississauga, Ontario, Canada) was used for evoking and recording the ASSR. Stimuli were 500 Hz tone bursts (10 ms, 82 dB peak equivalent sound pressure level) delivered to the right ear via the inserted earphone at the rate of 34–44 s. The stimulus rate producing the largest response during pretesting screening for a particular subject was chosen. A recording, with the right ear earphone disconnected (no stimulus), was also obtained to estimate baseline EEG noise. The EEG was recorded from T7, C5, C3, Cz, C4, C6, and T8, with reference to the right mastoid. The signal was amplified (bandpass, 0.1–300 Hz, model 12A5 amplifier; Grass Instrument Corp.), and the analog-to-digital conversion rate was adjusted to obtain 32 points/epoch (1 epoch = 1 ASSR cycle) that lasted 29.4–22.7 s, depending on the stimulus rate. Epochs contaminated by artifacts (±100 μV) were automatically rejected. For each assessment, we obtained 10 replicate averages. Each average, consisting of responses to 2,000 stimuli (responses automatically rejected as artifact were replaced), required 45–75 s and were stored on disk for off-line analysis. In one subject, the recordings were reformatted to have T7 as a reference instead of M2 to attenuate myogenic artifacts. Replicate averages that were clearly deviant from the others were eliminated during off-line review (number of discarded averages: 63 of 730 [8.3%]; maximum number of discarded average per subject = 3). The replicate averages were combined for each period and each subject to produce a single tracing (12–20,0000 stimuli). The amplitude and phase (relative to stimulus onset) of the ASSR were measured by fast Fourier transform of the single averaged tracings.
The BIS was recorded from electrodes placed at C3 and C4, with reference to the right mastoid using an A-1000 EEG Monitor (bandpass 1.0–30.0 Hz; Aspect Medical Systems, Natick, MA, software version 3.12). The electrodes were attached to the A-1000 monitor via “jumper” cables connected from the Grass model headstage. BIS was recorded before and after the block of 10 ASSR recordings. The mean of the two measures was used for analysis.
Back to Top | Article Outline
Statistics
Statistical analysis was performed with use of GraphPad InStat (version 2.0, GraphPad Software, San Diego, CA) unless otherwise indicated. Differences between recording periods were evaluated using analysis of variance for repeated measures. The Tukey honest significance difference test was used for post hoc comparisons. A two-tailed, paired t test was used to compare ASSR and BIS values obtained during baseline and unconsciousness. The comparison of duration of loss of consciousness before physostigmine administration was performed using a two-tailed, unpaired t test. Comparison of the ability of physostigmine versus saline and of physostigmine versus scopolamine pretreatment + physostigmine, to reverse the propofol-induced unconsciousness, were evaluated using 2-×-2 contingency tables and the Fisher exact test.
We adopted the prediction probability (Pk) method of Smith et al.33 (Excel, version 5, Microsoft Corp., Redmond, CA) to quantify the efficiency of the amplitude of the ASSR or the BIS to predict responsiveness to verbal commands. Pk is a nonparametric, rank-order measure of association, ranging from 0.5 (chance level) to 1.0 (perfect concordance). The Pk value was based on 73 observations for ASSR and BIS; all subjects and periods of recording were included. We calculated the standard error of the estimate with use of the jackknife approach, as if the observations were independent, as was done by Leslie et al.34
Results are expressed as mean ± SD, unless otherwise indicated. The criterion for statistical significance was P < 0.05.
Back to Top | Article Outline

Results

Reversal of Propofol-induced Loss of Consciousness by Physostigmine
Fig. 1
Fig. 1
Image Tools
Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools
The loss of consciousness and abolition of spontaneous movement was produced by propofol at a target plasma concentration of 3.1 ± 0.6 μg/ml (n = 17), which was similar to the measured plasma concentration of 3.2 ± 0.8 μg/ml (sample drawn after the 10-min equilibration period after loss of consciousness). The target and measured plasma concentrations of propofol differed by 16.4 ± 16.0%. Because of the persistence of spontaneous movement, target propofol concentrations had to be increased by 1 μg/ml from the concentration that produced loss of responsiveness to verbal commands in 4 of 17 subjects. Loss of consciousness was associated with the inability of the subjects to respond to the command “open your eyes” and “squeeze my fingers” and with the abolition of the EOG response (baseline awake: latency, 576.3 ± 297.8 ms; amplitude, 250.2 ± 138.1 μV;fig. 1). In addition, loss of consciousness was associated with reductions in the ASSR and BIS amplitudes compared with the awake baseline values (figs. 2 and 3).
Fig. 4
Fig. 4
Image Tools
Fig. 5
Fig. 5
Image Tools
Depending on the randomized order of physostigmine–saline (control) administration, physostigmine was administered 27.8 ± 12.4 (n = 5) or 70.7 ± 18.7 min (n = 6) after loss of consciousness and abolition of movement produced by propofol (51.2 ± 27.2 min for all 11 subjects). The propofol plasma concentration after the 10-min equilibration period after the loss of consciousness and mobility (3.3 ± 0.9 μg/ml) was similar to those before (2.9 ± 0.8 μg/ml) and after (3.0 ± 1.0 μg/ml) the time of administration of physostigmine or saline, indicating that the plasma propofol concentrations were stable during this period. Although saline was without effect (n = 5), physostigmine restored consciousness in 9 of 11 subjects (P = 0.004). Return to consciousness was determined by the reappearance of the EOG response to the verbal command “open your eyes” (latency: 687.5 ± 526.7 ms; amplitude: 60.11 ± 114.4 μV; n = 9;fig. 1). The physostigmine-induced return to consciousness was accompanied by an increase in the ASSR, which was greater than that recorded during the unconscious state but was similar to the baseline value and to that observed 30 min after discontinuation of propofol administration, when the subjects were fully awake, oriented, and conversant (figs. 2 and 4). The physostigmine-induced return to consciousness was also accompanied by an increase in the BIS, which was greater than that recorded during the unconscious state (fig. 5). The physostigmine-induced increase in the BIS was less than the baseline value and that observed approximately 30 min after discontinuation of propofol administration (fig. 5B).
Of the remaining 2 of 11 subjects in whom physostigmine did not reverse the propofol-induced loss of consciousness, 1 remained fully unresponsive, and the propofol-induced reductions in the ASSR and BIS were not reversed by administration of physostigmine (figs. 4A and 5A). In this subject, physostigmine was administered 20 min after onset of unconsciousness. The other subject followed commands in an equivocal manner, demonstrating uncoordinated movements to the verbal command. In this case, the propofol-induced reductions in the ASSR and BIS were reversed by physostigmine (figs. 4A and 5A). Physostigmine was administered 49 min after onset of unconsciousness.
Back to Top | Article Outline
Scopolamine Block of the Physostigmine-induced Return to Consciousness
Fig. 6
Fig. 6
Image Tools
In six additional subjects, scopolamine was administered after loss of consciousness, and abolition of movement produced by propofol and the ability of physostigmine to reverse the loss of consciousness was then studied 60 min after scopolamine administration. Physostigmine was administered 98.7 ± 13.5 min after the propofol-induced loss of consciousness, which was significantly greater than that for the subjects who did not receive scopolamine (P = 0.001). The plasma propofol concentrations after the 10-min equilibration period after the loss of consciousness and immobility (3.2 ± 0.6 μg/ml) and just before (3.0 ± 0.4) and after (3.0 ± 0.58) administration of physostigmine were similar, indicating that the plasma concentrations of propofol were stable during this period. Moreover, these concentrations were similar to those observed in patients who did not receive pretreatment with scopolamine before reversal of the loss of consciousness by physostigmine. Scopolamine blocked the physostigmine-induced reversal of unconsciousness in all six subjects, in marked contrast to the reversal of unconsciousness produced by physostigmine in 9 of 11 subjects reported previously herein (P < 0.002). Similarly, scopolamine pretreatment also prevented the recovery of the ASSR and BIS (fig. 6). Interestingly, scopolamine appeared to have no additional inhibitory effect on the ASSR and BIS, which were reduced during loss of consciousness and immobility produced by propofol administration (fig. 6). When subjects were fully awake, oriented, and conversant 30 min after discontinuation of propofol administration, the ASSR and BIS were similar to baseline levels (fig. 6).
Back to Top | Article Outline
Relation between Auditory Steady State Response, Bispectral Index, and Consciousness
Parallel changes in the sate of consciousness and amplitude of the ASSR and BIS produced by propofol, physostigmine, and scopolamine administration were observed. This is indicated by the high correlation of the amplitude of the ASSR (PK = 0.925; SEM = 0.033) and BIS (PK = 0.984; SEM = 0.011;P = NS) with the presence and absence of consciousness.
Back to Top | Article Outline

Discussion

This study shows that physostigmine, a carbamyl tertiary amine anticholinesterase that crosses the blood–brain barrier, reverses the propofol-induced unconsciousness and associated depression of the ASSR and BIS in human volunteers. Reversal of the loss of consciousness and depression of the ASSR and BIS produced by physostigmine was blocked by pretreatment with scopolamine, a nonselective muscarinic antagonist that also crosses the blood–brain barrier. These findings are consistent with the hypothesis that the loss of consciousness produced by propofol is mediated, at least in part, via interruption of central cholinergic muscarinic transmission.
To assess level of consciousness, we used responsiveness to verbal commands, which has been used previously. 35 To objectively measure responsiveness to the verbal command “open your eyes,” we recorded the EOG. The electroocculogram confirmed our subjective impressions but showed no increase in sensitivity. The requirement of a motionless subject necessitated that, in 4 of 17 subjects, the target propofol concentration be increased by 1.0 μg/ml from the previous dose, which produced loss of responsiveness to verbal commands. It can be argued, therefore, that with these four subjects (and, perhaps, with others) a greater dose of propofol was administered than that which just produces loss of consciousness.
The experimental design of a study in which human volunteers are used is constrained by safety issues related to the dose of drugs that can be administered. We considered it impractical to achieve steady state concentrations of physostigmine and scopolamine. As explained in the Methods section, the single bolus doses of physostigmine and scopolamine were chosen on the basis of their demonstrated clinical effectiveness to reverse the central cholinergic syndrome (physostigmine) or to depress cognitive function and produce sedation (scopolamine). Conversely, the rate of propofol infusion was titrated to produce loss of consciousness and abolition of spontaneous movement. Larger doses of propofol were not administered to help avoid depression of the sensorium beyond that which produces loss of consciousness. This had practical relevance, in that subjects were able to maintain spontaneous respiration despite unconsciousness. This also may have theoretical relevance because it is anticipated that with any drug there is a greater degree of nonselective action as the dose increases. Given these caveats, it is fortuitous that the single bolus doses of physostigmine and scopolamine were, in almost all cases, of sufficient magnitude such that they produced the intended effect, indicating that the dose–effect relations of the relevant endogenous ligands and receptors were amenable to these pharmacologic manipulations.
The reversal of the propofol-induced loss of consciousness by physostigmine is compatible with the hypothesis that propofol produces the loss of consciousness by interfering, directly or indirectly, with central cholinergic transmission. We did not, however, directly assess whether propofol alters such transmission. Therefore, we cannot discount the possibility that physostigmine may produce a return to consciousness, via enhancement of central cholinergic drive, by altering neuronal activity in a pathway or neuronal system not affected by propofol. For example, it is known that noxious stimulation may improve the level of consciousness in a sedated patient, 36 yet this cannot be interpreted as proof that the somnolence was produced by block of sensory input. Moreover, consideration must be given to the possibility that physostigmine may produce a return to consciousness by mechanisms other than inhibition of central cholinesterase activity. For example, it has been suggested that physostigmine and other carbamyl containing anticholinesterase drugs directly activate muscarinic receptors. 37
That scopolamine blocks the reversal of the loss of consciousness by physostigmine implicates muscarinic receptor subtypes. Of course, other possibilities must be considered. Again, we cannot discount the possibility that scopolamine alters neuronal activity in a pathway or neural system not affected by propofol, a possibility considered herein previously with physostigmine. Conceivably, propofol could mediate its effect on consciousness by interfering with nicotinic transmission, and the administration of scopolamine, via inhibition of central muscarinic transmission, simply augments the depth of anesthesia, such that physostigmine at the dose administered no longer reverses the loss of consciousness. However, scopolamine did not depress the ASSR or BIS beyond that produced by propofol, arguing against the possibility of a greater depth of anesthesia. If propofol mediates the loss of consciousness by block of central cholinergic muscarinic transmission, it may be anticipated that the addition of a muscarinic antagonist, such as scopolamine, should not further reduce transmission. This assumes that the block of central cholinergic transmission produced by propofol is at or near 100%.
Another consideration is that, in subjects pretreated with scopolamine, physostigmine was administered after a longer duration of unconsciousness than in those who did not receive the muscarinic antagonist. However, there was considerable overlap in the duration of unconsciousness in subjects pretreated with scopolamine (89, 89, 91, 92, 110, and 121 min) and in the non-pretreated subjects in whom unconsciousness was reversed by physostigmine administered after saline control (53, 54, 56, 82, 82, and 97 min), as dictated by the randomized administration protocol. The administration of scopolamine after achieving propofol-induced loss of consciousness ensured that the plasma concentration of propofol in this group was similar to that in the group of subjects that did not receive the muscarinic antagonist. Had the scopolamine been administered before propofol, then as a result of the additive CNS depressant effects, it is possible that a lower dose of propofol would have been necessary to produce unconsciousness. As reversal of the loss of consciousness by physostigmine would then have been evaluated in patients with different plasma concentrations of propofol, it would have been difficult to draw any inferences.
The site of action of propofol in the CNS to produce unconsciousness is not known. It has been proposed that cholinergic projections to the cortex and forebrain arising from the caudal mesencephalic–pontine reticular formation and the basal forebrain may play an important role in regulating the level of consciousness, 38,39 and one may speculate that propofol interferes with these projection systems. The mechanism of interference, too, is a matter of speculation. Evidence, as cited in the Introduction, suggests that propofol may directly interfere with cholinergic transmission. Alternatively, the effect may be indirect, involving other neurotransmitter and modulator substances. For example, it has been proposed that propofol acts by binding directly to the γ-aminobutyric acid receptor A (GABAA) chloride channel or to the channel regulatory proteins. 40
The close correlation of the amplitude of the ASSR and BIS with the presence or absence of consciousness, while propofol concentrations were held constant, suggest that these neurophysiologic measurements reflect CNS processes mediating consciousness rather than simply propofol concentration at CNS effector sites. In particular, that close correlations were observed when central cholinergic transmission was altered by block of cholinesterase activity or muscarinic receptors suggest that a neurophysiologic substrate mediating the ASSR and BIS involves cholinergic muscarinic processes. Muscarinic processes in the cortex 41 and thalamus 42 have been linked to the potentiation of endogenous γ oscillations. Enhancement of endogenous γ oscillations have been linked to states of high vigilance, 43,44 and generation of endogenous γ oscillations and the ASSR may involve similar cellular mechanisms. 45 The somewhat higher PK of the BIS compared with that of the ASSR indicates that the BIS may be more closely correlated to the presence or absence of consciousness. The possibility that BIS recordings may have been contaminated by electromyogram artifact cannot be discounted because subjects were not paralyzed. Such contamination is less of a concern with an evoked averaged response such as the ASSR.
In summary, we have shown that physostigmine reverses the propofol-induced unconsciousness and associated depression of the ASSR and BIS in human volunteers. The reversal of the unconsciousness and depression of the ASSR and BIS was blocked by pretreatment with scopolamine. These findings support the hypothesis that the loss of consciousness produced by propofol and, by analogy, other anesthetic drugs is mediated, at least in part, via interruption of central cholinergic muscarinic transmission.
The authors thank F. Varin, Ph.D., Professor, Faculty of Pharmacy, University of Montreal, Quebec, Canada, for the propofol assay; W.D. Smith, Professor, Biomedical Engineering, California State University, Sacramento, California, for the Excel macros for computation of Pk; Zeneca Pharma, Inc., Mississauga, Ontario, for donating the propofol; and the staff of the Clinical Investigation Unit and of the Recovery Room at the Royal Victoria Hospital for their generous assistance.
Back to Top | Article Outline

References

1. Durieux ME: Muscarinic signalling in the central nervous system: Recent developments and anesthetic implications. A nesthesiology 1996; 84: 173–89

2. Lydic R, Baghdoyan HA: Cholinergic contributions to the control of consciousness, Anesthesia: Biologic Foundations. Edited by Yaksh TL, Lynch C,III Zapole WM, Maze M, Biebuyck JF, Saidman LJ. Philadelphia, Lippincott–Raven, 1997, pp 433–50

3. Sagales T, Erill S, Domino EF: Differential effects of scopolamine and chlorpromazine on REM and NREM sleep in normal male subjects. Clin Pharmacol Ther 1969; 10: 522–9

4. Gillin JC, Sitaram N, Mendelson WB. Acetylcholine, sleep, and depression. Human Neurobiology 1982; 1: 211–9

5. Lydic R, Baghdoyan HA, Lorinc Z: Microdialysis of cat pons reveals enhanced acetylcholine release during state-dependent respiratory depression. Am J Physiol 1991; 261: R766–70

6. Baghdoyan HA, Spotts JL, Snyder SG: Simultaneous pontine and basal forebrain microinjections of carbachol suppress REM sleep. J Neurosci 1993; 13: 229–42

7. Ngai SH, Cheney DL, Finck AD: Acetylcholine concentrations and turnover in rat brain structures during anesthesia with halothane, enflurane, and ketamine. A nesthesiology 1978; 48: 4–10

8. Keifer JC, Baghdoyan HA, Lydic R: Pontine cholinergic mechanisms modulate the cortical EEG spindles of halothane anesthesia. A nesthesiology 1996; 84: 945–54

9. Kikuchi T, Wang Y, Sato K, Okumura F:In vivo effects of propofol on acetylcholine release from the frontal cortex, hippocampus and striatum studied by intracerebral microdialysis in freely moving rats. Br J Anaesthesia 1998; 80: 644–8

10. Mortazavi S, Thompson J, Baghdoyan HA, Lydic R: Fentanyl and morphine, but not remifentanil, inhibit acetylcholine release in pontine regions modulating arousal. A nesthesiology 1999; 90: 1070–7

11. Anthony BL, Dennison RL, Aronstam RS: Disruption of muscarinic receptor-G protein coupling is a general property of liquid volatile anesthetics. Neurosci Lett 1989; 99: 191–6

12. Dilger JP, Vidal AM, Mody HI, Liu L: Evidence for direct actions of general anesthetics on an ion channel protein. A new look at a unified mechanism of action. A nesthesiology 1994; 81: 431–42

13. Wachtel RE: Relative potencies of volatile anesthetics in altering the kinetics of ion channels in BC3H1 cells. J Pharm Exp Ther 1995; 274: 1355–61

14. Andoh T, Furuya R, Oka K, Hattori S, Watanabe I, Kamiya Y, Okumura F: Differential effects of thiopental on neuronal nicotinic acetylcholine receptors and P2X purinergic receptors in PC12 cells. A nesthesiology 1997; 87: 1199–209

15. Flood P, Ramirez-Latorre J, Role L: α4β2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but α7-type nicotinic acetylcholine receptors are unaffected. A nesthesiology 1997; 86: 859–65

16. Minami K, Vanderah TW, Minami M, Harris RA: Inhibitory effects of anesthetics and ethanol on muscarinic receptors expressed in Xenopus oocytes. Eur J Pharmacol 1997; 339: 237–44

17. Violet JM, Downie DL, Nakisa RC, Lieb WR, Franks NP: Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. A nesthesiology 1997; 86: 866–74

18. Rumack BH: Anticholinergic poisoning: Treatment with physostigmine. Pediatrics 1973; 52: 449–51

19. Granacher RP, Baldessarini RJ: Physostigmine: Its use in acute anticholinergic syndrome with antidepressant and antiparkinson drugs. Arch Gen Psychiatry 1975; 32: 375–80

20. Hill GE, Stanley TH, Sentker CR: Physostigmine reversal of postoperative somnolence. Can Anaesth Soc J 1977; 24: 707–11

21. Toro-Matos A, Rendon-Platas AM, Avila-Valdez E, Villarreal-Guzman RA: Physostigmine antagonizes ketamine. Anesth Analg 1980; 59: 764–7

22. Caldwell CB, Gross JB: Physostigmine reversal of midazolam-induced sedation. A nesthesiology 1982; 57: 125–7

23. Artru AA, Hui GS: Physostigmine reversal of general anesthesia for intraoperative neurological testing: Associated EEG changes. Anesth Analg 1986; 65: 1059–62

24. Smith DB, Clark RB, Stephens SR, Sherman RL, Hyde ML: Physostigmine reversal of sedation in parturients. Anesth Analg 1976; 55: 478–80

25. Fassoulaki A, Sarantopoulos C, Derveniotis Ch: Physostigmine increases the dose of propofol required to induce anaesthesia. Can J Anaesth 1997; 44: 1148–51

26. Plummer GF: Improved method for the determination of propofol in blood by high-performance liquid chromatography with fluorescence detection. J Chromatography 1987; 421: 171–6

27. Tackley RM, Lewis GT, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT: Computer controlled infusion of propofol. Br J Anaesth 1989; 62: 46–53

28. Schinder TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs EJ: The influence of age on propofol pharmacodynamics. A nesthesiology 1999; 90: 1502–16

29. Holford NHG: Physiological alternatives to the effect compartment model, Advanced Methods of Pharmacokinetic and Pharmacodynamic Systems Analysis. Edited by D’Argenio DZ. New York, Plenum Press, 1991, pp 55–9

30. Vitiello B, Martin A, Hill J, Mack C, Molchan S, Martinez R, Murphy DL, Sunderland T: Cognitive and behavioural effects of cholinergic, dopaminergic, and serotonergic blockade in humans. Neuropsychopharmacol 1997; 16: 15–24

31. Prohovnik I, Arnold SE, Smith G, Lucas LR: Physostigmine reversal of scopolamine-induced hypofrontality. J Cereb Blood Flow Metab 1997; 17: 220–8

32. Rosier A, Cornette L, Orban GA: Scopolamine-induced impairment of delayed recognition of abstract visual shapes. Neuropsychobiology 1998; 37: 98–103

33. Smith WD, Dutton RC, Smith NT: A measure of association for assessing prediction accuracy that is a generalization of non-parametric ROC area. Stat Med 1996; 15: 1199–215

34. Leslie K, Sessler DI, Smith WD, Larson MD, Ozaki M, Blanchard D, Crankshaw DP: Prediction of movements during propofol/nitrous oxide anesthesia. A nesthesiology 1996; 84: 52–63

35. Plourde G, Villemure C, Fiset P, Bonhomme V, Backman SB: Effect of isoflurane on the auditory steady-state response and on consciousness in human volunteers. A nesthesiology 1998; 89: 844–51

36. Munglani R, Andrade J, Sapsford DJ, Baddeley A, Jones JG: A measure of consciousness and memory during isoflurane administration: The coherent frequency. Br J Anaesth 1993; 71: 633–41

37. Stein RD, Backman SB, Collier B, Polosa C: Bradycardia produced by pyridostigmine and physostigmine. Can J Anaesth 1997; 44: 1286–92

38. Jones BE: Basic mechanisms of sleep-wake states, Principles and Practice of Sleep Medicine, 2nd edition. Edited by Kryger MH, Roth T. Philadelphia, WB Saunders, 1994, pp 145–62

39. Fiset P, Paus T, Daloze T, Plourde G, Meuret P, Bonhomme V, Hajj-Ali N, Backman SB, Evans AC: Brain mechanisms of propofol-induced loss of consciousness in humans: A positron emission tomographic study. J Neurosci 1999, 19: 5506–13

40. Orser BA, McAdam LC, Roder S, MacDonald JF: General anaesthetics and their effects on GABA(A) receptor desensitization. Toxicology Letters 1998; 100–101: 217–24

41. Metherate R, Cox CL, Ashe JH: Cellular basis of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine. J Neurosci 1992; 12: 4701–11

42. Steriade M, Dossi RC, Pare D, Oakson G: Fast oscillations (20–40Hz) in thalamocortical systems and their potentiation by mesopontine cholinergic nuclei in the cat. Proc Natl Acad Sci U S A 1991; 88: 4396–400

43. Steriade M: Central core modulation of spontaneous oscillations and sensory transmission in the thalamocortical systems. Curr Opin Neurobiol 1993; 3: 619–25

44. Steriade M, McCormick DA, Sejnowski TJ: Thalamocortical oscillations in the sleeping and aroused brain. Science 1993; 262: 697–85

45. Franowicz MN, Barth DS: Comparison of evoked potentials and high-frequency (gamma-band) oscillating potentials in rat auditory cortex. J Neurophysiol 1995; 74: 96–112

Cited By:

This article has been cited 63 time(s).

Journal of Neural Engineering
Burst suppression probability algorithms: state-space methods for tracking EEG burst suppression
Chemali, J; Ching, SN; Purdon, PL; Solt, K; Brown, EN
Journal of Neural Engineering, 10(5): -.
ARTN 056017
CrossRef
Journal of Neuroscience
The septohippocampal system participates in general anesthesia
Ma, JY; Shen, BX; Stewart, LS; Herrick, IA; Leung, LS
Journal of Neuroscience, 22(2): -.
ARTN RC200
CrossRef
Anesthesia and Analgesia
Dystonic reaction to propofol attenuated by benztropine (cogentin)
Schramm, BM; Orser, BA
Anesthesia and Analgesia, 94(5): 1237-1240.

Brain Research Reviews
The neurophysics of consciousness
John, ER
Brain Research Reviews, 39(1): 1-28.
PII S0165-0173(02)00142-X
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
The potential use of intralipid to minimize propofol's cardiovascular effects
Gragasin, FS; Davidge, ST; Tsui, BCH
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 56(2): 170-171.
10.1007/s12630-008-9031-4
CrossRef
Medicina Clinica
Club drugs: new departments challenges for the emergency departments
Abanades, S; Peiro, AM; Farre, M
Medicina Clinica, 124(6): 239.

British Journal of Anaesthesia
Antagonism of neuromuscular blockade but not muscle relaxation affects depth of anaesthesia
Vasella, FC; Frascarolo, P; Spahn, DR; Magnusson, L
British Journal of Anaesthesia, 94(6): 742-747.
10.1093/bja/aei120
CrossRef
Suppressing the Mind: Anesthetic Modulation of Memory and Consciousness
A Neurochemical Perspective on States of Consciousness
Watson, CJ; Baghdoyan, HA; Lydic, R
Suppressing the Mind: Anesthetic Modulation of Memory and Consciousness, (): 33-80.
10.1007/978-1-60761-462-3_3
CrossRef
Journal of Neurophysiology
Disruption of coherent oscillations in inhibitory networks with anesthetics: Role of GABA(A) receptor desensitization
Baker, PM; Pennefather, PS; Orser, BA; Skinner, FK
Journal of Neurophysiology, 88(5): 2821-2833.
10.1152/jn.00052.2002
CrossRef
International Journal of Audiology
Human auditory steady-state responses
Picton, TW; John, MS; Dimitrijevic, A; Purcell, D
International Journal of Audiology, 42(4): 177-219.

Anesthesiology
Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat
Dong, HL; Fukuda, S; Murata, E; Higuchi, T
Anesthesiology, 104(1): 122-132.

Nature Reviews Neuroscience
General anaesthesia: From molecular targets to neuronal pathways of sleep and arousal
Franks, NP
Nature Reviews Neuroscience, 9(5): 370-386.
10.1038/nrn2372
CrossRef
Psychosomatics
Dexmedetomidine and the Reduction of Postoperative Delirium after Cardiac Surgery
Maldonado, JR; Wysong, A; van der Starre, PJA; Block, T; Miller, C; Reitz, BA
Psychosomatics, 50(3): 206-217.

Toxicology
Effects of cholinergic overstimulation on isoflurane potency and efficacy in cortical and spinal networks
Grasshoff, C; Drexler, B; Antkowiak, B
Toxicology, 229(3): 206-213.
10.1016/j.tox.2006.10.017
CrossRef
Consciousness and Cognition
Identifying the neural correlates of consciousness: Strategies with general anesthetics
Plourde, G
Consciousness and Cognition, 10(2): 241-244.

Journal of Clinical Anesthesia
Anesthesia with 1.5 minimum alveolar concentration sevoflurane is not altered by physostigmine as measured by bispectral and clinical indices
Paraskeva, A; Staikou, C; Diamadis, M; Siafaka, I; Fassoulaki, A
Journal of Clinical Anesthesia, 17(8): 581-585.
10.1016/j.jclinane.2005.03.005
CrossRef
Synapse
PET quantification of muscarinic cholinergic receptors with [N-C-11-methy]-benztropine and application to studies of propofol-induced unconsciousness in healthy human volunteers
Xie, GM; Gunn, RN; Dagher, A; Daloze, T; Plourde, G; Backman, SB; Diksic, M; Fiset, P
Synapse, 51(2): 91-101.

Minerva Anestesiologica
Sevoflurane as a single anesthetic and physostigmine failure to enhance arousal
Paraskeva, A; Petropoulos, G; Siafaka, I; Fassoulaki, A
Minerva Anestesiologica, 72(): 821-826.

Critical Care Clinics
Delirium in the Acute Care Setting: Characteristics, Diagnosis and Treatment
Maldonado, JR
Critical Care Clinics, 24(4): 657-+.
10.1016/j.ccc.2008.05.008
CrossRef
Anasthesiologie & Intensivmedizin
How do anaesthetics act?
Tonner, PH
Anasthesiologie & Intensivmedizin, 47(): 265-+.

Suppressing the Mind: Anesthetic Modulation of Memory and Consciousness
Cortical Disintegration Mechanism of Anesthetic-Induced Unconsciousness
Hudetz, A
Suppressing the Mind: Anesthetic Modulation of Memory and Consciousness, (): 99-125.
10.1007/978-1-60761-462-3_5
CrossRef
Annals of Emergency Medicine
Use of physostigmine in the management of gamma-hydroxybutyrate overdose - In reply
Kuhn, M; Caldicott, D
Annals of Emergency Medicine, 38(3): 347-348.

Sleep
Ketamine and MK-801 decrease acetylcholine release in the pontine reticular formation, slow breathing, and disrupt sleep
Lydic, R; Baghdoyan, HA
Sleep, 25(6): 617-622.

Acetylcholine in the Cerebral Cortex
Cholinergic mechanisms mediating anesthetic induced altered states of consciousness
Backman, SB; Fiset, P; Plourde, G
Acetylcholine in the Cerebral Cortex, 145(): 197-206.
10.1016/S0079-6123(03)45014-0
CrossRef
Anesthesia and Analgesia
Physostigmine does not antagonize sevoflurane anesthesia assessed by bispectral index or enhances recovery
Paraskeva, A; Papilas, K; Fassoulaki, A; Melemeni, A; Papadopoulos, G
Anesthesia and Analgesia, 94(3): 569-572.

British Journal of Anaesthesia
In vivo characterization of clinical anaesthesia and its components
Antognini, JF; Carstens, E
British Journal of Anaesthesia, 89(1): 156-166.

Annales Francaises D Anesthesie Et De Reanimation
Automatic EEG analysis for monitoring depth of anaesthesia in year 2000
Billard, V; Constant, I
Annales Francaises D Anesthesie Et De Reanimation, 20(9): 763-785.

Behavioural Brain Research
Subhypnotic doses of propofol accelerate extinction of conditioned taste aversion
Ishitobi, S; Miyamoto, T; Oi, K; Toda, K
Behavioural Brain Research, 141(2): 223-228.
PII S0166-4328(02)00375-3
CrossRef
Anesthesia and Analgesia
Orexin A elicits arousal electroencephalography without sympathetic cardiovascular activation in isoflurane-anesthetized rats
Yasuda, Y; Takeda, A; Fukuda, S; Suzuki, H; Ishimoto, M; Mori, Y; Eguchi, H; Saitoh, R; Fujihara, H; Honda, K; Higuchi, T
Anesthesia and Analgesia, 97(6): 1663-1666.
10.1213/01.ANE.0000089964.85834.EF
CrossRef
Anaesthesia, Pain, Intensive Care and Emergency Medicine - Apice 19
Neuroimaging pharmacology of attention and memory
Freo, U; Ori, C
Anaesthesia, Pain, Intensive Care and Emergency Medicine - Apice 19, (): 217-225.

Acta Anaesthesiologica Scandinavica
Do patients profit from physostigmine in recovery from desflurane anaesthesia?
Rohm, KD; Riechmann, J; Boldt, J; Schollhorn, T; Piper, SN
Acta Anaesthesiologica Scandinavica, 51(3): 278-283.
10.1111/j.1399-6576.2006.01238.x
CrossRef
British Journal of Anaesthesia
Muscle relaxation and depth of anaesthesia: where is the missing link?
Bonhomme, V; Hans, P
British Journal of Anaesthesia, 99(4): 456-460.
10.1093/bja/aem243
CrossRef
British Journal of Anaesthesia
Opposite effects of depressant and convulsant barbiturate stereoisomers on acetylcholine release from the rat hippocampus in vivo
Inagawa, G; Sato, K; Kikuchi, T; Nishihama, M; Shioda, M; Koyama, Y; Yamada, Y; Andoh, T
British Journal of Anaesthesia, 92(3): 424-426.
10.1093/bja/aeh070
CrossRef
Endoscopy
Combining physostigmine with meperidine for sedation and analgesia during colonoscopy
Yardeni, IZ; Melzer, E; Smolyarenko, V; Zeidel, A; Chervinsky, A; Binder, Y; Beilin, B
Endoscopy, 37(): 1205-1210.
10.1055/s-870217
CrossRef
Toxicology
Atropine increases sevoflurane potency in cortical but not spinal networks during cholinergic overstimulation
Drexler, B; Antkowiak, B; Thiermann, H; Grasshoff, C
Toxicology, 268(): 98-103.
10.1016/j.tox.2009.12.005
CrossRef
Journal of Emergency Medicine
Antimuscarinic syndrome after propofol administration in the emergency department
Snow, KA; Clements, EA; Eppert, AJ; Judge, BS
Journal of Emergency Medicine, 33(1): 29-32.
10.1016/j.jemermed.2007.02.045
CrossRef
Journal of Anesthesia
Aminophylline reversal of prolonged postoperative sedation induced by propofol
Sakurai, S; Fukunaga, A; Fukuda, K; Kasahara, M; Ichinohe, T; Kaneko, Y
Journal of Anesthesia, 22(1): 86-88.
10.1007/s00540-007-0587-x
CrossRef
Critical Care Clinics
Pathoetiological Model of Delirium: a Comprehensive Understanding of the Neurobiology of Delirium and an Evidence-Based Approach to Prevention and Treatment
Maldonado, JR
Critical Care Clinics, 24(4): 789-+.
10.1016/j.ccc.2008.06.004
CrossRef
Toxicology
Anaesthesia in patients suffering from organophosphorus intoxication - interactions between general anaesthetics and acetylcholine in cortical networks in vitro
Grasshoff, C; Thiermann, H; Antkowiak, B
Toxicology, 233(): 214-222.
10.1016/j.tox.2006.09.001
CrossRef
Consciousness and Cognition
Replies to commentaries
John, ER
Consciousness and Cognition, 10(2): 246-258.
10.1006/ccog.2001.0517
CrossRef
British Journal of Anaesthesia
Antagonism of sevoflurane anaesthesia by physostigmine: effects on the auditory steady-state response and bispectral index
Plourde, G; Chartrand, D; Fiset, P; Font, S; Backman, SB
British Journal of Anaesthesia, 91(4): 583-U1.
10.1093/bja/aeg209
CrossRef
Neurocomputing
Modulation of coherent oscillations in inhibitory networks by anesthetics
Baker, PM; Skinner, FK
Neurocomputing, 44(): 293-299.
PII S0925-2312(02)00355-7
CrossRef
Anaesthesia
Physostigmine for the prevention of postanaesthetic shivering following general anaesthesia - a placebo-controlled comparison with nefopam
Rohm, KD; Riechmann, J; Boldt, J; Schuler, S; Suttner, SW; Piper, SN
Anaesthesia, 60(5): 433-438.

Advances in Modelling and Clinical Application of Intravenous Anaesthesia
Functional brain imaging and propofol mechanisms of action
Fiset, P
Advances in Modelling and Clinical Application of Intravenous Anaesthesia, 523(): 115-121.

British Journal of Anaesthesia
Partial antagonism of propofol anaesthesia by physostigmine in rats is associated with potentiation of fast (80-200 Hz) oscillations in the thalamus
Reed, SJ; Plourde, G; Tobin, S; Chapman, CA
British Journal of Anaesthesia, 110(4): 646-653.
10.1093/bja/aes432
CrossRef
Journal of Clinical Monitoring and Computing
The effect of atropine on the bispectral index response to endotracheal intubation during propofol and remifentanil anesthesia
Kwak, HJ; Moon, BK; Oh, CK; Chang, YJ; Kim, HS; Kim, JY
Journal of Clinical Monitoring and Computing, 27(2): 157-161.
10.1007/s10877-012-9407-4
CrossRef
Anesthesiology
Effect of Propofol on Carotid Body Chemosensitivity and Cholinergic Chemotransduction
Jonsson, MM; Lindahl, SG; Eriksson, LI
Anesthesiology, 102(1): 110-116.

PDF (508)
Anesthesiology
Attenuation of the 40-Hertz Auditory Steady State Response by Propofol Involves the Cortical and Subcortical Generators
Plourde, G; Garcia-Asensi, A; Backman, S; Deschamps, A; Chartrand, D; Fiset, P; Picton, TW
Anesthesiology, 108(2): 233-242.
10.1097/01.anes.0000299839.33721.6d
PDF (1008) | CrossRef
Anesthesiology
Dialysis Delivery of an Adenosine A1 Receptor Agonist to the Pontine Reticular Formation Decreases Acetylcholine Release and Increases Anesthesia Recovery Time
Tanase, D; Baghdoyan, HA; Lydic, R
Anesthesiology, 98(4): 912-920.

PDF (1416)
Anesthesiology
Involvement of the Basal Cholinergic Forebrain in the Mediation of General (Propofol) Anesthesia
Laalou, F; de Vasconcelos, AP; Oberling, P; Jeltsch, H; Cassel, J; Pain, L
Anesthesiology, 108(5): 888-896.
10.1097/ALN.0b013e31816d919b
PDF (731) | CrossRef
Anesthesiology
Cholinergic Modulation of Sevoflurane Potency in Cortical and Spinal Networks In Vitro
Grasshoff, C; Drexler, B; Hentschke, H; Thiermann, H; Antkowiak, B
Anesthesiology, 106(6): 1147-1155.
10.1097/01.anes.0000267598.65120.f2
PDF (1237) | CrossRef
Anesthesiology
Thalamic Microinjection of Nicotine Reverses Sevoflurane-induced Loss of Righting Reflex in the Rat
Alkire, MT; McReynolds, JR; Hahn, EL; Trivedi, AN
Anesthesiology, 107(2): 264-272.
10.1097/01.anes.0000270741.33766.24
PDF (846) | CrossRef
Anesthesiology
Morphine Inhibits Acetylcholine Release in Rat Prefrontal Cortex When Delivered Systemically or by Microdialysis to Basal Forebrain
Osman, NI; Baghdoyan, HA; Lydic, R
Anesthesiology, 103(4): 779-787.

PDF (745)
Anesthesiology
General Anesthesia and Ascending Arousal Pathways
Zecharia, AY; Franks, NP
Anesthesiology, 111(4): 695-696.
10.1097/ALN.0b013e3181b061bc
PDF (85) | CrossRef
Anesthesiology
Cholinergic Reversal of Isoflurane Anesthesia in Rats as Measured by Cross-approximate Entropy of the Electroencephalogram
Hudetz, AG; Wood, JD; Kampine, JP
Anesthesiology, 99(5): 1125-1131.

PDF (747)
Anesthesiology
Halothane-induced Hypnosis Is Not Accompanied by Inactivation of Orexinergic Output in Rodents
Gompf, H; Chen, J; Sun, Y; Yanagisawa, M; Aston-Jones, G; Kelz, MB
Anesthesiology, 111(5): 1001-1009.
10.1097/ALN.0b013e3181b764b3
PDF (1403) | CrossRef
Anesthesiology
Cholinesterase Inhibitors, Neuromuscular Blocking Drugs and Perioperative Memory Enhancement
Fodale, V; Tescione, M; Praticò, C
Anesthesiology, 101(6): 1483-1484.

PDF (431)
Anesthesiology
Sleep, Anesthesiology, and the Neurobiology of Arousal State Control
Lydic, R; Baghdoyan, HA
Anesthesiology, 103(6): 1268-1295.

PDF (2526)
Anesthesiology
Opioid-induced Decreases in Rat Brain Adenosine Levels Are Reversed by Inhibiting Adenosine Deaminase
Nelson, AM; Battersby, AS; Baghdoyan, HA; Lydic, R
Anesthesiology, 111(6): 1327-1333.
10.1097/ALN.0b013e3181bdf894
PDF (840) | CrossRef
Clinical Neuropharmacology
Intravenous Subhypnotic Propofol in Central Pain: A Double-Blind, Placebo-Controlled, Crossover Study
Canavero, S; Bonicalzi, V
Clinical Neuropharmacology, 27(4): 182-186.

PDF (68)
European Journal of Anaesthesiology (EJA)
Doxapram and aminophylline on bispectral index under sevoflurane anaesthesia: a comparative study
Wu, CC; Lin, CS; Wu, GJ; Lin, YH; Lee, YW; Chen, JY; Mok, MS
European Journal of Anaesthesiology (EJA), 23(11): 937-941.
10.1017/S0265021506001220
PDF (83) | CrossRef
Otology & Neurotology
Evaluation of a Novel, Noninvasive, Objective Test of Auditory Nerve Function in Cochlear Implant Candidates
Gräbel, S; Hirschfelder, A; Scheiber, C; Olze, H
Otology & Neurotology, 30(6): 716-724.
10.1097/MAO.0b013e3181b0fe48
PDF (771) | CrossRef
Anesthesiology
Scopolamine Prevents Dreams during General Anesthesia
Toscano, A; Pancaro, C; Peduto, VA
Anesthesiology, 106(5): 952-955.
10.1097/01.anes.0000265154.24685.47
PDF (152) | CrossRef
Back to Top | Article Outline
Keywords:
Awareness; EEG; anticholinesterase.

© 2000 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.